2-aminomethylene-3-oxo steroids and preparation thereof



3,265,686 Z-AMINOh'llC'llll/LENPIG-0X0 STEROIDS AND PREPARATION THEREOF Raymond 0. Clinton, East Greenhush, N.Y., assignor to Sterling Drug inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 27, i960, Ser. No. 4,882

30 Claims. (Ci. 260-2395) B=NC(R)= wherein B=N is a basic amino radical, and R represents hydrogen or a lower-alkyl radical.

The exact nature of the steroid moiety is not critical.

'The utility of steroids, including those exhibiting hormonal or other pharmacological or endocrinological properties, is well-known. Such steroid moieties have from seventeen to about twenty-three carbon atoms,'not counting carbon content which may be provided by esterified hydroxy groups. Esterified hydroxy-steroids are included Within the scope of the invention, but the carbon content contributed by the acid moiety of the ester is not considercd part of the essential carbon content of the steroid.

The steroid moiety can be any member of the androst-ane, etiocholane, pregnane or allopregnane series. The foregoing can contain varying degrees of unsaturation and a. variety of substituents in the form of hydrocarbon radicals or functional groups conventionally employed in the steroid art. Representative of the steroid moieties which make up the compounds of the invention are those having at position 17 a hydroxy, aeyloxy, x0, or both a hydroxy and a lower-alkyl radical, characteristic of the androgenic and anabolic steroids; or a lower-alkenyl, lower-alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl, l-hydroxyethyl, and the like radicals, optionally together with a hydroxy group at C characteristic of the progrestational and adrenal cortical steroids. The steroid moiety can also have one or more substituents at other positions of the nucleus, for example, hydroxy, aeyloxy, or 0x0 radicals at positions 6, 7, ll, 12, 14 or 16; halogen atoms, preferably fiuorine or chlori-ne, for example, at the 4-, 6-, 7-, 9- 12- or Ill-positions; and lower-alkyl groups, for example, at the 4-, 6-, 7-, 11- or l6-positions. The steroid moiety can also have one or more double bonds, especially at the 4,5- and/or 6,7-positions. The steroid moiety usually possesses angular methyl groups at C and C although 18- and 19-nor-steroids and 18,19-bisnor-steroids, lacking one or both of the angular methyl groups at C and C respectively, are also contemplated.

The 18,19-bisnor-steroid, 18- or l9-nor-steroid, and normal steroid moieties in the compounds of the invention contain respectively, seventeen, eighteen and nineteen carbon atoms plus any carbon content which may be provided by one or more nuclearly substituted hydrocarbon radicals, up to and including a total of about twenty-three carbon atoms.

When acyloxy radicals are present in the steroid moiety, the acyl radicals are preferably derived from carboxylic acids having from one to about ten carbon atoms, conventionally employed in the steroid art, and having a molecular weight less than about 200. Representative of the acyl radicals which can be present are lower-alkanoyl radicals, e.g., forrnyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl and the like; carboxy-lower-alkanoyl radicals, e.g., suceinyl (/3- Patented August 9, 1966 carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., ti-cyclopcntylpropionyl, /3-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals. e.g., benzoyl, ptoluyl, p-nitrobcnzoyl, 3,4,5-1rimcthoxybenzoyl, and the like; monocarbocyclie aryl-lovrer-alkanoyl or -alkenoyl radicals, such as phcnylncetyl, fi-phenylpropionyl, cinnamoyl, and the like; and monocarbocyclic aryloxy-loweralkanoyl radicals, such as p-ehlorophenoxyaeetyl, and the like. Esters of inorganic acids such as phosphoric acid are also contemplated.

In the Z-(I-aminoalkylidene) substituent the portion B=N stands for primary amino (H N) or a. basic secondary or tertiary amino radical having a molecular weight less than about 200. By a secondary amino radical is meant a radical of the type YHN wherein Y is an organic substituent so that the complete molecule to which it is attached is a secondary amine. By a tertiary amino radical is meant a radical of the type YYN- wherein Y and Y are both organic substituents so that the complete molecule to which it is attached is a tertiary amine. Basic amino radicals are those of the aliphatic or araliphatic type that impart to the molecules which contain them sufficient basicity so that the compounds readily form acid-addition salts with strong inorganic and organic acids. A particularly preferred group of amino radicals are primary amino (H N); lower-alkylamino, for example, methylamino and ethylamino; cycloalkylamino in which the cycloalkyl has from 3 to 7 ring members, for example, cyclopropylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino; phenyl-lower-alkylamino, for example, benzylamino and phenylcthylamino; di-loweralkylamino, for example, dimethylamino and diethylamino; dicycloalkylamino in which cycloalkyl has from 3 to 7 ring members, for example, dicyclopentylamino and dicyclohexylamino; N-(cycloalkyl)-lower-alkylamino in which the cycloalkyl has from 3 to 7 ring members, for example, N-rnethylcyclohexylamino and N-ethylcyclopentylamino; polymethylenimino having from 5 to 7 ring members, for example, l-pyrrolidyl, l-piperidyl, hexamethylenimino and lower-alkylated derivatives thereof; 4- morpholinyl; di-(phenyl-lower-alkyl)amino, for example, dibenzylamino and bis(phenylethyl)amino; N-(phenyllower-alkyl)-lower-alkylamino, for example, N-benzylmethylarnino; di-loWer-alkylamino-loWer-alkylamino, for example, di-methylaminoethylamino; and polymethylenimino-lower-alkylamino, for example, l-piperidylethylamino. In the foregoing radicals, the term lower-alkyl stands for alkyl groups containing from one to about six carbon atoms with the additional proviso that in the dilower-alkylamino-lower-alkylamino and polyrnethylenimino-lower-alkylamino radicals, the two nitrogens are separated by at least two carbon atoms.

The compounds of the invention are prepared by reacting a 2-(l-hydroxyalkylidenel-3-oxo-steroid with ammonia or a basic amine, B=NH, according to the following equation:

wherein Q represents the remaining portion of the steroid moiety described above. The condensation takes place by heating the 2-( l-hyclroxyalkylidene)-3-oxo-steroid with at least one molar equivalent of the amine B N-H in an inert solvent or reaction medium at a temperature between about 50 C. and C. The nature of the inert solvent is not critical, although hydrocarbon solvents such as benzene, toluene or xylene, or lower-alkanols, e.g., ethanol are preferred.

35 A particularly preferred group of compounds comprises 2-(l-aminoalkylidene)-3-oxo-steroids of the androstane or etiocholane series, in which the steroid moiety has from seventeen to about twenty-three carbon atoms exclusive of ester radicals, including those having the structural formula wherein R represents hydrogen or lower-alkyl; R represents hydrogen, lower-alkyl, lower-alkenyl, lower-alkenyl, acetyl, ketalized acetyl, hydroxyacetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl or l-hydroxyethyl; X is selected from the group consisting of H (H)(OH) and O; Y and Y represent hydrogen or methyl; Z represents hydrogen or hydroxy, Z being restricted to hydroxy when R represents hydrogen, lower-alkyl, lower-alkenyl or lower-alkynyl; and B N represents primary amino, or basic secondary and tertiary amino having a molecular weight less than about 200. Also contemplated are carboxylic acid esters of the compounds possessing hydroxy groups, as well as those having one double bond in the 4,5-psltion (Formula II below), and those having two double bonds, one in the 4,5-position and the other in the 6,7-position (Formula IIa below):

X Y Q Meta The compounds of Formulas I, II and Ila are preared by reacting the appropriate 2-(l-hydroxyalkyliene)-3-oxo-steroid, viz.:

Y Z If. Y HOC= (III) or the corresponding compounds where a double bond is present in the l.5-position or two double bonds in the 4,5- and 6.7-po-.itions. with an amine B NH: B N. R. R, X. Z, Y and Y having the same meanings given above. except that when the steroid moiety contains oxo groups in addition to the one at position 3. preferably protected as n ketal derivative to prevent possible side reactions with the amine and especially to perniit formation of the intermediate hydroxyalkylidene compound without aeylation in positions other than the Z-position. For example, when compounds in which R represents acetyl or hydroxyacetyl are desired, these radicals are preferably ketalized by known methods, e.g., with ethylene glycol, prior to introduction of the hydroxyalkylidene radical at the 2-position and reaction with an amine. The Ztl-monoketals of 3,20-dioxosteroids are prepared from the 3,20-diketals by selective hydrolysis by known methods. e.g.. by allowing the diketal to stand at room temperature in acetone solution containing a trace of p-toluenesulfonic acid. The ketal glOlpS are readily cleaved by dilute acid either before or after the condensation with an amine. Alternatively, ZO-monoketals of 3,20-dioxosteroids are produced by preparing the ZQ-ketal of a 3-hydroxy-ZO-oxosteroid and oxidizing the 3-hydroxy group to a 3-oxo group by means of chromic oxide in pyridine. It has been found, however, that 3,20-dioxosteroids bearing hydroxy groups at the 17- and 2l-positions can be selectively formylated in the Z-position without protecting the 20-oxo group by ketalization, particularly if the ZI-hydroxy group is etherified with a trityl Or pyranyl radical. An oxo group at the 11- position is relatively unreaetive and need not be proteeted before reaction with an amine or a derivative thereof.

As a variant on ketal formation, in the case where R is hydroxyacetyl and Z is OH, characteristic of cortisone and related cortical hormones, the side chain can be protected against formylation by first converting the compound to the 17,20: 20.2l-hismethylenedioxy derivative by reacting it with formaldehyde in the presence of strong acid by known methods.

The compounds of the invention are useful as intermediates in the preparation of different species within the scope of the invention by introduction of new groups or alteration of groups already present in the steroid nucleus by known methods. For example, a Z-(l-aminoalkylidene)-steroid having a hydroxy group in the 17- position of the steroid nucleus can be oxidized to the corresponding l7-oxo compound. As another instance, a eompotmd having a l-hydroxyethy'l radical in the 17- position [I or II; R is (I-I CH(OH)-, Z is H or OH] can be oxidized to the corresponding 17-acetyl compound [I or II; R is CH CO, Z is H or OH].

The intermediate 2-(l-hydroxyalkylidene)-3-oxo-steroids are prepared by condensing a 3-oxo-steroid with a lower-alkyl lower-alkanoate. RCOOR", wherein R is hydrogen or lower-alkyl and R" is lower-alkyl in the presence of a strong base under anhydrous conditions. The strong base is preferably an amide or hydride. An acyl group enters the 2-position with elimination of a molecule of an alcohol as follows:

II II n R-co RCOOR Q i Q R"OII The Z-acyl steroid in solution isin tautomerie equilibrium with its enol form (hydroxyalkylidene, HO-C(R)=), and the latter form is the one chosen for convenience in the structural formulas given elsewhere in this specification.

In the ease wherein the radical R is lower-alkyl an alternative and preferred method comprises treating the 3- oxosteroid with a lower-alkanoic acid anhydride in the presence of boron trifluoride. Steroids containing a 17-.

they are alkali metal lower-alkoxidef hydroxy group, particularly the l7-hydr0xy17-alkyl steroids,,can be protected against dehydration by prior esterification. The 2 (l hydroxyalkylidene) 3-oxosteroids are disclosed in my copending application, Serial No. 793,292, filed February 16, 1959.

The compounds of the invention are basic in character and will form acid-addition salts upon addition of strong acids. Those compounds which are tertiary-amines will also form quaternary ammonium salts upon addition of esters of strong acids. These salts are the full equivalent of the corresponding free bases insofar as their physiological properties are concerned. Both the free base and salt forms are considered to be one and the same invention.

The acid-addition salts are prepared by causing the 2- (l-aminoalkylidene)-steroid to react with a strong inorganic or organic acid, usually in an inert solvent or reaction medium. Examples of appropriate acids include hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, quinic, benzenesulfonic acid, and the like.

The quaternary ammonium salts of the compounds of the invention are prepared by causing a Z-(l-tertiaryaminoalkylidene)steroid to react with an ester of a strong inorganic or organic sulfonic acid, said ester preferably having a molecular Weight less than about 200. A particularly preferred class of esters, because of their ready availability, are lower-alkyl, lower-alkenyl and monocarbocyclic aryl-loWer-alkyl esters, for example, methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, butyl bromide, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, cychlorobenzyl chloride, and the like. The reaction of the 2-(l-tertiary-aminoalkylidene)-steroid and the quaternizing agent takes place upon simple admixture of the components, preferably in the presence of an inert organic solvent, although heating may be applied to accelerate the reaction.

The acid-addition and quaternary ammonium salts preferably have anions which are pharmacologically acceptable, that is, the anions do not appreciably increase the toxicity of the compound as a whole toward animal organisms. Such anions include, for example, the chloride, bromide, iodide, sulfate or acid sulfate, methanesulfonate, benzenesulfonate, and the like. Salts having toxic anions are, however, useful in that they serve as characterizing derivatives of the 2(l-aminoalkylidcne)-steroid, and serve as intermediates for non-toxic quaternary salts by conventional ion exchange reactions. All acid-addition salts, regardless of the nature of the anions, are useful as intermediates in the purification of the free bases.

Endocrinological studies of the compounds of the in vention have shown that they possess useful metabolic, hormonal and anti-hormonal properties. In particular they exhibit anabolic and pituitary inhibiting activities. Anabolic agents are useful in the treatment of conditions arising from poor nitrogen utilization. Pitutary inhibiting agents are useful in the treatment of endocrinological disorders brought about by hormonal imbalance.

Pharmacological evaluation has demonstrated that compounds of the invention also possess hypotensive properties thus indicating their usefulness in lowering blood pressure.

The compounds of the invention can be prepared for use by dispersing them in an aqueous suspension or by dissolving them in a pharmacologially acceptable oil or oil-water emulsion for parenteral administration; or by incorporation in tablet form with excipients for oral ad ministration.

The structure of the compounds of the invention was established by the mode of synthesis, their ultraviolet and infrared spectra, and by the fact that the values found upon elementary analysis corresponded with the values calculated for the assigned structures.

The following examples will further illustrate the invention without the latter being limited thereby.

6 EXAMPLE I 2 [(1 pyrrolidyl)methylene] 4-nnclrostcn-I 713-01-3- one [11; R is H, R is H, X is H Y and Y are CH Z is OH, B=N is (CH N].

A mixture of 11.7 g. of Z-hydroxymethylene-4-androsten-17fi-ol-3-one, 2.11 g. of pyrrolidine and ml. of benzene was refluxed for three hours in a Bidwell-Sterling moisture trap apparatus to collect the water formed in the reaction. The reaction mixture was concentrated in vacuo, the residue dissolved in benzene, and the benzene solution washed with 5% potassium hydroxide solution and concentrated in vacuo. The residue was dissolved in benzene and chromatographed on a column of 450 g. of basic alumina. The column was eluted with the solvent series benzene-ether-methanol. Elution with ether-methanol (99:1) brought out the crystalline product, which when recrystallized first from acetone and then from an acetone-methanol mixture and dried at 80 C. for twentyfour hours in vacuo gave 2-[(1-pyrrolidyl)methylene]-4- androsten-l7B-0l-3-one in the form of yellow-orange prisms, M;P. 2l4.0225.6 C. (corn), [a] =-50.8 (1% in chloroform); ultraviolet maxima at 250 and 372 In (E=17,600 and 15,300).

Analysis.Calcd. for C H NO C, 78.00; H, 9.55; N, 3.79. Found: C, 77.93; H, 9.54; N, 3.71.

2"[ l-pyrrolidyl)methylene]-4-an-drosten-l7B-o]-3 one reacts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, quinic acid, naphthalenesulfonic acid, methyl iodide, ethyl bromide, allyl bromide, benzyl chloride, or 2-chlorobenzyl chloride to give the hydrochloride, hydrobromide, sulfate (or bisulfate), phosphate (or acid phosphate), tartrate (or bitartrate), quinate, naphthalenesulfonate, methiodide, ethobromide, allobromide, benzochloride, or 2-chlorobenzochloride salts, respectively.

2 [(1 pyrrolidyl)methylene] 4 androsten ol-3-one can be reacted with acetic anhydride, proptionic anhydride, caproyl chloride, succinic anhydride, ,8 cyclopentylpropionyl chloride, benzoyl chloride, p-nitrobenzoyl, chloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride, or cinnamoyl chloride, "by heating in the presence of pyridine, to give, respectively,

I 17fl-cinnamoyloxy-2- l-pyrrolidyl) methylene] -4- androsten-3-one.

EXAMPLE 2 2 [(n hexyDaminomethylene] 4 androsten 17B- 0l3-0ne [II; B=N is C-H (CH NH] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of n-hexylamine.

EXAMPLE 3 2 (benzylaminomethylene) 4 androsten 17,8 ol- 3-0ne [I]; B=N is c H CH Nl-l] can be prepared by re placing the pyrrolidine in Example 1 by a molar equivalent amount of benzylam ine.

7' EXAMPLE 4 2 (cyclopropyIaminomelhylene) 4 anrh'osten 17/8- l-3-0ne [11; B N is (CH CHNH] can be prepared by vreplacing the pyrrolidine in Example 1 by a molar equivalent amount of cyclopropylamine.

EXAMPLE 2 (cyclohexylaminomethylene) 4 androslen 17;?- 0l-3-0ne [11; B N is (CH CHNH] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of cyclohexylamine.

EXAMPLE 6 2 (cycloheptylaminomethylene) 4 androsten 17(3- ol-3-one [11; B N is (CH CHNH] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of cycloheptylamine.

' EXAMPLE 7 2 (dicyclohexylaminomethylene) 4 androsten 17B- 0l-3-0ne [II; B N is (C H N] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of dicyclohexylamine.

EXAMPLE 8 2 [N (cyclohexyl)methyhiminomethylene] 4 andr0sterz-17/8-ol-3-one [11; B N is (C H )(CH )N] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of N-(cyclohexyl)methylamine.

EXAMPLE 9 I 4-androslen-17fi-0l-3-0ne [11; B N is 3,4- (CH O) C H CH CH NI-1] can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of fi-(3,4-dimethoxyphenyl)ethylamine.

EXAMPLE 12 2 [B hydroxy B (4 hydrvxyphenyl)ethylaminomethylene]-4-andr0sten-17fl-0l-3-0ne [I'I; B N is can be prepared by replacing the pyrrolidine in Example 1 by a molar equivalent amount of 3-hydroxy-fl-(4-hyd-roxyphenyl)ethylamine.

EXAMPLE 13 2 [2 (I piperidyl)ethylamilwmethylene] 4 andr0sten-l7/3-ol-3-one [11; B N is (CH NCH CH NH] can be prepared by replacing the pyrrol-idine in Example 1 by a molar equivalent amount of 2-(1-piperidyl)ethylamine.

EXAMPLE 14 2 [(1 pyrr0lidyl)methylene] 17a methylawdrostan-17fi-0I-3-0ne [1; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (CH N] was prepared from 3.00 g. of 2-hydroxymethylene-17a-methyland1'ostan- 17fl-ol-3-one and 1 ml. of pyrrolidine in 200 m1. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 3.17 g. of 2-[(l-pyrrolidyDmethylene]-17a-methylandrostan-17/3-ol-3-one, which after three recrystallizations from ethyl acetate and drying at C. for eight hours in vacuo had the M.P. 224.2-231.6 C.,

( 1% in chloroform); ultraviolet maximum at 339 mp (E=23,400).

Analysis.Calcd. for C H NO C, 77.87; H, 10.20; N, 3.63. Found: C, 77.99; H, 9.92; N, 3.63.

2 [(1 pyrrolidyl)methylene] 17a methylandrostan-l7t3-ol-3-one, when tested by the method of Minatoya et al., Arch. Internat. de Pharmacodynamie et de Therapie, 108, 10228 (1956), was found to be an active hypotensive agent at a dose level of 200 nag/kg, producing a maximum fall of 32.8 mm. Hg in blood pressure after twenty-four hours, when administered orally as an aqueous suspension in renal hypertensive rats.

EXAMPLE 15 2 [(1 hexamelhylenimino)methylenc] 17cc methylandrostan 175 ol 3 one [1; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (CH N] was prepared from 5.00 g. of Z-hydroxymethylene-17a-methylandrostan-l7B-ol-3-one and 1.65 g. of hexamethylenimine in 300 ml. of benzene according to the manipulative procedure described above in Example 1. The product was recrystallized successively from methanol, ethyl acetateether, ethyl acetate and methanol-ether and dried at 85 C. for eight hours in vacuo to give 2-[(l-hexametl1ylenimino)methylene] -17a methyland-rostan 17/9 ol 3- one, M.P. 219.0-222.6 C. (corn), [a] =2O5.O (1% in chloroform); ultraviolet maximum at 334 m (E=23,300).

Analysis.-Calcd. for C H NO C, 78.40; H, 10.48; N, 3.39. Found: C, 78.70; H, 10.43; N, 3.40.

EXAMPLE 16 2 [(1 piperidyl)methylene] 17a methylandrostan- I7/J-0l-3-0ne [1; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (CH N].

A mixture of 1.8 g. of 2-hydroxymethylene-17a-methylandrostan-17,8-ol-3-one, 1.7 g. of piperidine, 25 m1. of acetone and 1.2 g. of acetic acid was refluxed for seventytwo hours. The product which separated upon cooling the reaction mixture was collected by filtration, and the 1.55 g. of product was recrystallized from ethanol and dried at 80 C. for eight hours in vacuo to give 2- [(1 piperidyl)methylene]-l7a-methylandrostan 17B- ol-3-one in the form of yellow plates, M.P. 232.0239.2 C., [a] ==--266.8 (1% in chloroform).

Analysis.Calcd. for C26H41NO2: C, 78.14; H, 10.34; N, 3.51. Found: C, 77.98; H, 10.07; N, 3.43.

EXAMPLE 17 2 [(2 diethyIaminoethylamino)meI/Iylene] 1701- mcthyl-4-andr0slen-17B-0I-3-0ne [II; R is H, R is CH X is H Y and Y are CH Z is OH, B N is was prepared from 5.00 g. of Z-hydroxymethylene-lhmethyl-4-androsten-17fi-ol-3-one and 1.93 g. of 2-diethylaminoethylamine in 200 ml. of benzene according to the manipulative procedure described above in Example 1. The 4.21 g. of product, M.P. 175 C. (uncorn), thus obtained was chromatographed on 180 g. of alumina and then recrystallized successively from acetone, ethermethanol and acetone and dried at 90 C. for eight hours in vacuo to give 2-[(2-diethylaminoethylamino)methylene]-17a-methyl-4-androsten-l7fl-ol-3-one, M.P. 181.4- 184.4 C. (corr.), [a] =101.5 O.4 (1% in chloroform); ultraviolet maxima at 248 and 366 mu (E==16,320 and 14,700).

Analysis.-Calcd. for C H N O C, 75.65; H, 10.35; N, 6.54. Found: C, 75.90; H, 10.12; N, 6.4-6.

EXAMlLE 1s methyl-l-piperidyl)-methylene] 17oz methyl 4 androsten-17f3-ol-3-one, M.P. 1996-2142 C. (corr.), when recrystallized twice from acetone, [a] =-322.9 :03 (1% in chloroform); ultraviolet maxima at 248 and 373 m (E=l7,400 and 15,200).

Analy.ri.r.--Calcd. for CgqHnNOz: C, 78.78; H, 10.04; N, 3.40. Found: C, 78.61; H, 9.81; N, 3.41.

EXAMPLE l9 2-(diethylaminoelllylene)etiocholan 17B ol 3 one [I; R is H, R is H, X is H Y and Y are CH Z is OH, B N is (C H N] was prepared from 4.9 g. of 2-hydroxymethyleneetiocholan-l7fi-ol-3-one and 1.5 g. of diethylamine in 75 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 3.9 g. of Z-(diethylaminomethylene)etiocholan-17fl-ol-3-one, M.P. 18l.6l88.4 C. (corr.) when recrystallized from ether, [u] =+232.4 (1% in chloroform); ultraviolet maximum at 333 mp. (E=2l,500).

Arzalysis.--Calcd. for C H NO C, 77.18; H, 10.44; N, 3.75. Found: C, 77.25; H, 10.74; N, 3.72.

2(diethylaminomethylcne)etiocholan-l7B-0l 3 one, when tested by the method of Minatoya et al., loc. cit., showed an average drop of 3235 mm. Hg in blood pressure after four to six hours when administered orally to rats at dose levels of -100 mg./kg. Upon subcutaneous administration similar effects were obtained at dose levels of 25-10 mg./kg. The hypotensive effect was of long duration.

EXAMPLE 20 2 (dfelhylaminomelhylene) 17cc methyletiocholan- ]7fl-ol-3-0lie ['l; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (C H N] was prepared from Z-hydroxymethylene 17a methyletiocho'lan-l7fiol-3-one and diethylamine according to the manipulative procedure described above in Example 1. The product was obtained in the form of pale yellow prisms, M.P. 176.4l80.2 C. (c0rr.) when recrystallized from acetone and dried at 80 C. for fifteen hours in vacuo, [e] =+]95.6 $0.1 (1% in chloroform); ultraviolet maximum at 333 my. (E=22,600).

A.izalysis.Calcd. fOr C25H41NO21 C, H, N, 3.61; O, 8.26. Found: C, 77.80; H, 10.55; N, 3.60; O, 8.40.

EXAMPLE 21 2 [(1 piperidyhmethylene] 17a-m-ethyletiacholan- 17fi-0l-3-0ne [1; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (CH N] was prepared from Z-hydroxymethylene 17a methyletiocholan 1719-01-3- one and piperidine according to the manipulative procedure described above in Example 1. The product was recrystallized from acetone to give 2-[(l-piperidyl) methylene] 17a-methyletiocholan-17B-ol-3-one in the form of pale yellow short needles, M.P. 1902-1980 C. (corn), [e] -=+236.3 (1% in chloroform); ultraviolet maximum at 334 m (E=21,900).

Analysis-Called. for C H NO C, 78.18; H, 10.34; N, 3.50. Found: C, 78.21; H, 10.31; N, 3.44.

2-[( 1-piperidyl)methylene] 17oz methyletiocholan- 17,8-ol-3-one, when tested by the method of Minatoya et al., 'loc. cit., showed an average drop of 13 mm. Hg in blood pressure when administered orally to rats at a'dose level of 100 mg./kg.

10 EXAMPLE 22 Z-(di n-butylaminomerhylene)-]7mmelhyletiocholan- 175-013-0122 [1; R is H, R is CH X is H Y and Y' are CH Z is OH, B N is (n-C H N] was prepared from Z-hydroxymethylene 17a methyletiocholan-17flol-3l-o1ie and di-n-butylamine according to the manipulative procedure described above in Example 1. The product was recrystallized twice from an ether-pentane mixture to give 2-(di n butylaminomethylene)-l7etmethyletiocholan-l7,6-ol-3-one in the form of pale yellow short needles, M.P. l40.4143.2 C. (corn),

(1% in chloroform); ultraviolet maximum at 334 mg (E 23,200).

Anal vris.-Calcd. for C ,,H NO C, 78.48; H, 11.13;

yletioclmlmz-I7,6-0I-3-0ne [1; R is H, R is CH X is H Y and Y' are CH Z is OH, B N is 3-acetamido-lpiperidyl] was prepared from 2-hydroxymethylene-17amethyletiocholan-17B-ol-3-one and 3-acetamidopiperidine according to the manipulative procedure described above in Example 1. The product was recrystallized twice from ether to give 2-[(3-acetamido-1-piperidyl)methylene]- 17e-methyletiocholan-17B-ol-3-one in the form of a pale yellow powder, M.P. l39.8l47.0 C. (corn),

( 1% in chloroform); ultraviolet maximum at 334 mu (E=17,600).

A.rzaIysis.-Cal6d. for C H N O C, 73.66; H, 9.64; N, 6.13. Found: C, 73.42; H, 9.40; N, 5.93.

EXAMPLE 24 2 (dibenzylaminomelliylene) I7ot-methyletiocholan- I7fl-0l-3-0ne [1; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (C H CH N] was prepared from 2 hydroxymethylene-l7a-methyletiocholan-175-01- 3-onc and dibenzylamine according to the manipulative procedure described above in Example 1. The product was recrystallized twice from ether to give 2-(dibenzylaminomethylene) l7ot-methyletiocholan-17fi-ol-3-one in the form of pale yellow short needles, M.P. l57.0-l6l.4 C. (corn), [e] =+48.1 (1% in chloroform); ultraviolet maximum at 332 m (E=2l,900).

Analysis.Calcd. for C H, NO C, 82.15; H, 8.87; N, 2.74. Found: C, 82.47; H, 8.85; N, 2.71.

EXAMPLE 25 2 [(I-pyrrolidyl)methylene]-4-mzdr0stene-3,I7-dione can be prepared by oxidizing 2-[(l-pyrrolidyl)methylene]-4-androsten-17B-ol-3-one (Example 1) with a solution of chromic oxide in pyridine at room temperature. The product is isolated by adding the reaction mixture to water, extracting the product with ethyl acetate and concentrating the ethyl acetate solution.

EXAMPLE 26 2-[2 (IJmmmetliylcnimino)propylnminomerliylene]- I7a-methyl-4-andr0stcn-I7,3-0I-3-0ne [II; R is H, R is CH X is H Y and Y' are CH Z is OH, B N is (CH NCH CH CH NH] was prepared from 5.00 g. of Z-hydroxymethylene-17u-methyl-4-androsten-l7/3-ol-3-one and 2.36 g. of 2-(l-hexamethylenimino)propylamine in 200 ml. of benzene according to the manipulative procedure described above in Example 1. The product was obtained in the form of an oil.

EXAMPLE 27 2 amiimmethylene I 7e-merhyI-4-androsten-I 7,8-olone [II; R is H, R is CH X is H Y and Y are CH Z is OH, B N is H N].

A rapid stream of dry ammonia gas was passed into a solution of 6.60 g. of Z-hydroxymcthylene-l7u-methyl- 4-androsten-17fl-ol-3'-one in 200 ml. of chloroform at room temperature. After the solution was nearly saturated with ammonia, the solution was closed with a calcium chloride tube and allowed to stand at room temperature for eighteen hours. The reaction mixture was concentrated in vacuo, and the residue triturated with n-pentane and dried at 50 C. to give 6.71 g. of Z-aminomethylene- 17a-methyl-4-androsten-17fi-ol-3-one, M.P. 225-240 C. (uncorr.). A sample of the compound when recrystallized from a benzene-ethanol mixture was obtained in the form of yellow needles, M.P. 272277 C. (uncorr.); ultraviolet maxinia at 246 and 352 m (E=l4,300 and 10,300).

Analysis.Calcd. for C H O N: C, 76.55; H, 9.48; N, 4.25; O, 9.71. Found: C, 76.51; H, 9.17; N, 4.05; O, 9.60.

EXAMPLE 28 2-amirz0methyleneandroslan-I7/8-0l-3-0ne [1; R is H, R is H, X is H Y and Y are CH Z is OH, B N is H N] can be prepared by reacting Z-hydroxymethyleneandrostan-17fl-ol-3-one with ammonia according to the manipulative procedure described above in Example 27.

' 2 aminomethyleneandrostan-17/9-ol-3one when recrystallized from ethanol with benzene added had the M.P. 256- 259 C. (uncorr.); ultraviolet maximum at 315 m (E:15,300).

Analysis.-Calcd. for C H O N: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.91; H} 9.94; N, 4.17.

EXAMI 'LE 29 2 aminomelhylene-I 7a-methylandrostmz-l7fl-0l-3-0ne [1; R is H, R is CH X is 1-1 Y and Y are CH Z is OH, B N is H N] can be prepared by reacting 2-hydroxymethylene 17a-methylandrostan-17/8-ol-3-one with ammonia according to the manipulative procedure described above in Example 27. 2-aminomethylene-17emethylandrostan-17fi-ol-3-one when recrystallized from ethanol had the M.P. 272--274 C. (uncorr.); ultraviolet maximum at 315 m (E=1-4,600).

AnaIysis.-Calcd. for C H O N: C, 76.09; H, 10.03; N, 4.23. Found: C, 75.91; H, 10.00; N, 4.12.

EXAMFLE 3O Z-aminomelhylene-4-andr0sten-I7B-0l-3-0ne [11; R is H, R is H, X is H Y and Y are CH Z is OH, B N is H N] can be prepared by reacting 2-hydroxymethylene-4- androsten-17/3-ol-3-one with ammonia according to the manipulative procedure described above in Example 27. 2-aminomethylene4-androsten-17;3-ol-3-one when recrystallized from ethanol had the M.P. 252-260 C. (dec.) (uncorr.); ultraviolet maxima at 246 and 352 mp. (E:18,300 and 13,100).

Analysis.Calcd. for C H NO C, 76.15; H, 9.27; N, 4.44. Found: C, 76.01; H, 8.89; N, 4.13.

EXAMPLE 31 EXAMPLE 32 2 [(1 pyrrolidyl)methylene]androslan-I7fl-ol-3-mze [1; R is H, R is H, X is H Y and Y are CH Z is OH,

B N is (CH N] can be prepared by replacing the 2- hydroxymcthylcnc-4-undroslcn-l7p-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethyleucandrostaml7;i-ol-3-onc.

EXAMPLE 33 2 [(II-pyrrulid \llnudity/cue]-17a-cIllylmm'rosmn-i7pol-34mu [l; R is H, R is C 11 X is H Y and Y are CH Z is OH, B N is (CH MNJ can be prepared by replacing the 2-hydroxymethylene-4-androsten-17p-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-l7a-cthylandrostan-l7ti-ol-3-one.

EXAMPLE 34 2 [(I pyrrolidyl)methylene]-I704-0thyl-4-mzdroslcn- 1713-01-3-0ne [11; R is H, R is C 11 X is H Y and Y are CH Z is OH, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten- 17fi-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene-17a-ethyl-4-androsten-17 3-01-3- one.

EXAMPLE 35 2 [(1 pyrrolidyl)methylene]-I7a-vinyl-4-androsten- 17t3'0l-3-0ne [11; R is H, R is CH CH, X is 1-1 Y and Y are CH Z is OH, B N is (CH N] can be pre pared by replacing the 2-hydroxymethylene-4-androstenl7fi-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene-l7ot-vinyl-4-androsten-175-01-3- one.

EXAMPLE 36 2 [(1-pyrrolidyl)methylene]-17a-ethynyl-4-m1dr0sten- 17,8-ol-3-0ne [11; R is H, R is CHEC, X is H Y and Y are CH Z is OH, B N is (CH N] can be prepared by replacing the Z-hydroxymethylene-4androsten-l75-01- 3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 17a-ethynyl-4-andros-ten-17601-3- one.

EXAMPLE 37 2 [(1 pyrr'olia'yl)methylene]-4-pregnen-20,8-0I-3-0ne [11; R is H, R is CH CH(OH), X is H Y and Y are CH Z is H, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4 androsten--01-3- one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4-pre-gnen-20fi-ol-3-One.

EXAMPLE 3 8 2 [(1 pyrrolidyl)methylene]-4-pregnenc-3,20-dione [11; R is H, R is CH CO, X is H Y and Y are CH Z is H, B N is (CH N] can be prepared by oxidizing 2-[ l-pyrrolidyl)methylene]-4-pregnen-20fl-ol-3-one with chrornic oxide in pyridine.

EXAMPLE 39 2 [(1 pyrrolidyl)methylene]-17a-methyI-4,6-andr0- stadien-17fi-oI-3-one [1121; R is H, R is CH X is H Y and Y are CH Z is OH, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-l7a-methyl-4,6-andro- 'stadien-17}8-ol-3-one.

EXAMPLE 40 2 [(I-pyrr0lidyl) methylene]4,6-andr0sladien-I75-01-3- one [1Ia; R is H, R is H, X is H Y and Y' are CH Z is OH, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7fi-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-4,6-androstadien-17,8-ol-3-one.

EXAMPLE 41 2 [(I-pyrrolidyl)methylene]-4,4,I7ot-trimethyl-5-(mdrosten-Ufl-ol-B-one can be prepared by replacing the Z-hydroxyme-thylene-4-androsten-17p-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene- 4,4,17a-trimethyI S-andrQsLen-I7 3-o1-3-one.

13 EXAMPLE 42 2 l I-pyrmlic1yl)nzelhylrlze]-17ot-m('tl1yI-19410211111111)- stun-I713-01-342/10 II; R is H, R is CH X is H Y is CH Y is M, Z is OH, B N is (CH Nl can be prepared by replacing the 2-hydroxymcthylene-4-androsten-l7p-ol-3-onc in Example 1 by a molar equivalent amount of Z-hydroxymelhylene-17a-methyl-l9-norandroslan-l7fl-ol-3-one.

EXAMPLE 43 Z is OCOCH B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-l73-01-3- one in Example 1 by a molar equivalent amount of 2- acetyl-17p-acetoxyandrostan-3-one.

EXAMPLE 44 2-[I-( I pyrrolidyl)buIylizlcndandmstan-17fl-0l-0ne [1; R is CH (CH R is H, X is H Y and Y' are CH Z is OH, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17/3-0l-3-one in Exam plel by a molar equivalent amount of Z-(n-butyryl) androstan-17 3-ol-3-one.

EXAMPLE 45 2 [(I-pyrrolidyl)methylene] -4,4-dimelhyl--andr0slen- 17,6-0I-3-0ne can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7fl-o-3-one in Example 1 by a molar equivalent amount o1 2-hydroxymethylene-4,4-dimethyl-S-andros-ten-l7B-ol-3-one.

, EXAMPLE 46 2 [(I-pyrrolidyl)methylene]-4,4,l7tx-trimethylandroslan-I7fi-0l-3-0ne can be prepared by replacing the 2- hydroxymethylene-4-androsten-17p-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4, 4,]7tz-trimethylandrostan-17fl-ol-3-one,

EXAMPLE 47 2'- [tl-pyrrolidyl)methylene]-6u,I7u-rlimethyl-Landmsten-l 7p-ol-3-one can be prepared by replacing the 2- hydroxymethylenel-androste n-I7fl-ol-3-one in Example 1 by a molar equivalent amount of Z-hydrQXymethylene-Sa, l7a-dimethyl l-androstenl 7/3-ol-3-one,

EXAMPLE 48 2 [tI-pyrr0lidyl)melhylene]allopregnene,IO-dione [1; R is H, R is CH3C0, X is H Y and Y are CH Z is H, Bi=N is (CH N] can be prepared by replacing the Z-hydroxymethylene-4-androsten-l7/3-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethyleheallopregnane-3,20-dione 20-ethylene glycol ketal and then hydrolyzing the ketal group by heating With dilute acetic acid.

EXAMPLE 49 2 [(I-pyrr0lidyl)methylene]-4-pregnerte-I7a,2I-di0l- 3,II,20-tri0ne [II; R is H, R is CH (OH)CO, X is O, Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androstenl7 3-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4-pregnene-17a,21-diol-3,11,20- trione.

EXAMPLE 50 .2 [(bpyrrolidyl)methylene]-4-pregnene-17u,2I-di0l- 3,11,20-trione can also be prepared by replacing the 2- hydroxymethylene-4-androsten-17,8-01-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene- 4 pregnene-l7a,211-diol-3,11,20 trione 17,20;20,21-bismethylenedioxy derivative and heating the resulting product with dilute formic acid to remove the bismethylenedioxy group.

EXAMPLE 51 2 [(I-pyrrolia'yl)methylene]-4,4-dimethyI-5-pregnene- 3,20-dione can be prepared by replacing the 2-hydroxy- 2 ['(I-pyrrolidyl)methylene]-4-pregnene-20,2I-di0l-3- one [11; R is H, R is CH (OH)CH(OH), X is H Y and Y are CH Z is H, B N is (CH N] can be prepared by replacing the 2-hydroxymethylene-Landrosten- 17fi-ol-3-0ne in Example 1 by a molar equivalent amount of Z-hydroxymethyleneA-pregnene-20,21-diol-3-one.

EXAMPLE 54 2 (l-pyrrolidyl) methylene] -9-flu0r0-4-pr6gn9ne-17a 21-di0l-3,11,20-tri0ne can be prepared by replacing the 2-hydroxymethylene-4-androsten l7fi ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene- 9 fluoro-4-pregnene17a,2l-diol-3,11,20-trione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acid.

EXAMPLE 55 2 {(1 pyrrolidyl)methylene]-4-pregnene-I6a,l7a,21- rriol-3,20-dione 9/8,] I fl-oxide can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7fl-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 4 pregnene 16a,l7n,2l-triol-3,20-dione 9,3, llfl-oxide 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 5 6 2 [(1 pyrrolidyl)methylene]-4-pregncue-20,21-di01- 3-0ne 20,21 -acet0rzide can be prepared by replacing the 2- hydroxymethylene-4-androsten-17fl-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4- pregnene-20,2l-diol-3-one 20,2l-acetonide.

EXAMPLE 57 2 [(1 pyrrolidyl)methylene] -4,6-pregnadiene-I7u, 2I-diol-3,II,20-tri0ne lIla: R is H, R is HOCH CO, X is O, Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the Z-hydroxymethylene-4-androsten-17B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-4,6-pregnadiene-l7a,21- diol-3,ll,20-trione 20-m0noethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 58 2 [(I pyrrolia'yl)methylene]-4-pregnene-17:1,2I-di0l- 3,20-di0ne [II; R is H, R is HOCH CO, X is H Y and Y are CH Z is OH, B=N is (CH N'l can be prepared by replacing the Z-hydroxymethylene-4-androsten-175-01-3- one in Example 1 by a molar equivalent amount of 2-' hydroxymethylene-4-pregnene-17a,2l-diol-3,20-dione 20- monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 59 2 [(1 pyrrolidyl)methylene] 6-meIhyI-4-pregnene- 17a,2I-di0l-3,II-20-1ri0ne can be prepared by replacing the 2-hydroxymethylene-4-androsten-17fi-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene 6 methyl-4-p-regnene-l7a,2 l-diol-3,l LZOatrione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

153 EXAMPLE 60 2 [(l pyrrolidyl)methylene] 9 -fluro-6-melhyl-4- pregnene-17a,21-di0l-3,II,20-trione can be prepared by replacing the 2-hydroxymethylene-4-androsten-17B-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene 9 fluoro-6-methyl-4-pregnene-l7a,2l-dio1-3, 11,20-trione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 61 2 [(1 pyrrolidyl)methylene]-4-pregnene-16a,17 x,2ltriol-3,11,20-tri0ne can be prepared by replacing the 2- hydroxymethylene-4-androsten-l7 3-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4- pregnene-l6a,l7o ,2l-triol-3,11,20-trione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

2 [(1 pyrrolidyl)methylene] -]7a-ethynyl-4-andr0- sten-I7fl-0l-3-1l-a'i0ne [II; R is H, R is CHEC, X is O, Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17fl-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-l7otethynyl-4-androsten- 17/3-o1-3,11-dione.

EXAMPLE 65 2 [(l-pyrrolidyl)methylene]-17u-metlzyI-4-androsterzl7fi-ol-3Jl-dione [11; R is H, R. is CH X is O, Y and Y are CH Z is OH, B N is (CH N] can be prepared by replacing the Z-hydroxymcthylenel-androsten-l7,8-01- 3-one in Example 1 by a molar equivalent amount of 2- hydroxymethylene 17a methyl-4-androsten-17,B-ol-3,l ldione.

EXAMPLE 66 2 [(1 pyrr0liclyl)melhylene] -4-m1dr0s1en-17,8-0l-3, II-diOne llii; R is H, R is H, X is O, Y and Y are CH Z is OH, B N is (CH MN'I can be prepared by replacing the Z-hydroxymethylenel-an(lrosten-l'lfi-ol-3-one in EX- ample l by a molar equivalent amount of Z-hydroxymethylcne-4-androsten-17/8-ol-3 ,1 l-dione.

EXAMPLE 67 2 [(I pyrrolidyl)mclhylene] 4 andr0s!ene-6[i,17/3- a'z'oI-3-0ne can be prepared by replacing the Z-hydroxymethylene-4-androsten-l7 8-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-4-androstene-6fl,l7/3-diol-3-one.

EXAMPLE 68 2 [(1 pyrroll'dyl) methylene] 17:! methyl-4-andr0- stale-66,I7fi-di0l-3-0v2e can be prepared by replacing the 2-hydroxymethylene-4-androsten17fi-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylenel7a-methyl-4-androstene-6fl,l7fl-di0l-3-one.

EXAMPLE 69 2 [(1 pyrrolidyl)metlzylene]-4-andr0stevze-14a,17}8- diol-J-one can be prepared by replacing the Z-hydroxymethylcne-4-androsten-17ti-ol-3-one in Example 1 by -a molar equivalent amount of Z-hydroxymethylene-4-androstene-l4a,17fi-diol-3one.

l 6 EXAMPLE 70 2 [(1 pyrrolirlyl)methylene] I6fl methyl-4-mn1rnstmz-17/i-0I-3-0ne can be prepared by replacing the 2- hydroxymethylene-4-androsten-l7B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene- 16fi-methyl-4-androsten-l7 3-ol-3-one.

EXAMPLE 71 2 [(I pyrroh'dyl)methylene]-4-andr0sIene-IIa,I7,6- di0l-3-0ne [II; R is H, R is H, X is (H)(OH), Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the Z-hydroxymethylene-4-androsten-l7,8-01-3- one in Example 1 by a molar equivalent amount of 2- hydroxyrnethylene-4-androstene-l la, 1 7B-diol-3-one.

EXAMPLE 72 2 [(1 pyrroh'r/yl)methylene]-]9-n0r-4-andr0stene-6fi, 17fl-r1i0l-3-0ne can be prepared by replacing the 2-hydroxymethylene-4-androsten-17fl-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene-l9- nor-4-androstene-6fi,l7 i-diol-3-one.

EXAMPLE 73 2 [(I pyrrolidyl)methylene] -4-br0m0-J7a-metlzyl- 4-andr0slon-I7/3-0I-3-one can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7 3-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 4-bromo-l7a-methyl-4-androsten-17 3ol-3-one.

EXAMPLE 74 2 [(I --pyrr0lidyl)methylene]-4-melhyl-4-andr0sren- I7B-0l-3-one can be prepared by replacing the Z-hydroxymethylene-4-anclrosten-l7,B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylentf-4-methyl-4-androsten-l7fi-ol-3-one.

EXAMPLE 75 2 [(1 pyrrolidyl)methylene] 17oz etlzynyl 4,6- androstadien-I7/8-0l-3-0ne [Hag R is H, R is HCEC, X is H Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4- androsten-17B-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 17a ethynyl 4, o-androstadien-17,6-ol-3-one.

EXAMPLE 76 2 [(1 pyrrolidyl)methylene]allopregmuze 6B,]7zx, 21-tri0I-3,20-dione can be prepared by replacing the 2- hydroxymethylene-4-androsten-17,6-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethyleneallopregnane 6,8,l7a,2l triol 3,20 di-one 20 monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 77 2 [(1 pyrrolidyl)methylene] 4 prr'gmne 12a, I7a,21-tri0l-3,20-di0ne can be prepared by replacing the 2 hydroxymethylene 4 androsten 17B ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 4 pregnene 12a,170z .2l triol 3,20 dione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 78 2 [(1 pyrrolidyi)methylene]allopregmum 17a,21- diol-3,12,20-tri0ne can be prepared by replacing the hydroxymethylene 4 androsten 176 ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxymethyleneallopregnane 17a,21 diol 3,12,20 trione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

7 EXAMPLE 79 2 [(1 pyrrolidyl)methylene] 4,1I-pregnndirne-3, ZO-dione can be prepared by replacing the Z-hydroxymethylene 4 androsten 17 3 ol 3 one in Example 1 by a molar equivalent amount of 2-hydroxy-methylene- 4,11 pregnadiene 3,20 dione 20 monoethylene glycol ketal and hydrolyziug the ketal group by heating with dilute acetic acid.

EXAMPLE 80 2 [(1 pyrrolidyl)methylene] pregnen 17aoI-3,20-dione [11; R is H, R is CH C0, X is H Y and Y are CH Z is OH, B=N is (Cl-l N] can be prepared by replacing the 2 hydroxymethylene 4 androsten- 17B-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 4 pregnen 17oz ol 3,20- dione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE s1 2 [(1 pyrrolidyl)methylene] 17a methyl 4- pregnene-3,20-dine can be prepared by replacing the 2- hydroxymethylene 4 androsten 17B ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 17a methyl 4 pregnene 3,20 dione 20-monoethylene glycol ketal and-hydrolyzing the ketal group by heatihg with dilute acetic acid.

EXAMPLE 82 2 [(1 pyrroliclyhmethylene] 4 pregnen 6/8 ol- 3,20-dione can be prepared by replacing the Z-hydroxymethylene 4 androsten 17a ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxy-methylene- 4 pregnen 6/? ol 3,20 dione 20 monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 83 2 [(1 pyrrolidyl)melhylenc] 4 pregrzene 7,8, 11,3 diol 3,20 dione can be prepared by replacing the 2 hydroxymethylene 4- androsten 17,8 ol 3 one in Example 1 by a molar equivalent amount of 2-hydroxymethylene 4 pregnene 7B,llfi diol 3,20 dione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 84 2 [(1 pyrrolidyDmel/zylene1 12a chloro 4- pregnene-I7at,2l-di0l-3,1[JO-Mane can be prepared by replacing the 2 hydroxymethylene 4 androstenl'7B-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 12o: chloro 4 pregnenel7e,2l diol 3,11,20 trione 20 monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 85 2 [(1 pyi'mlt'dyDmethyIene] 18,19 bisnor 4- prgrzene-3,Z0-dione [11; R is H, R is CHQCO, X is H Y and Y are H, Z is H, B=N is (CH N] can be prepared by replacing the 2 hydroxymethylene 4 androsteu-l7B-ol-3-one in Example l by a molar equivalent amount of 2 hydroxymethylene 18,19 bisnor 4- prcgnene-3,20-dione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 86 2 [(1 pyfrolidynmethylene] 4 bromo 4 pregmane-17e,21-diol-3,11,20-trione can be prepared by replacing the 2 hydroxymethylene androsten 17,3- ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 4 bromo 4 pregnene 17cc, 21 diol 3,11,20 trione 20 monothylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 87 2 [(1 pyrrolidyhmethylene] 4 pregnene 7a, I2a-di0l-3,20-dione can be prepared by replacing the 2- liydroxymethylene 4 androsten 17p ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxy- 18 methylene 4 7 pregnene 70:,12ot diol 3,20 dione 20-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 88 2 -'[(1 7 pyrrolidyl)methylene1all0prcgnane 3,7,20- trione can be prepared by replacing the Z-hydroxymethylene 4 androsten 17B o1 3 one in Example 1 by a molar equivalent amount of 2-hydroxyrnethyleneallopregnane 3,7,20 trione 7,20 bis(ethylene glycol ketal) and hydrolyzing the ketal groups by heating with dilute acetic acid.

EXAMPLE 89 2 [(1 pyrrolidyDmel/rylene] 17a etlzylana'rosmn- 17fi-0I-3,7-di0ne can be prepared by replacing the 2- hydroxymethylene 4 androsten 17,8 ol 3 one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 17a ethylandrostan 17/3 ol 3,7 dione 7-mon0ethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 90 2 [(1 pyrrolia'yl)methylene]allopregnane 3,7 dione can be prepared by replacing the 2-hydroxymethylene 4 androstcn 17,3 ol 3 one in Example 1 by a molar equivalent amount of 2-hydroxymethyleneallopregnane-3,7'dione 7-monoethylene glycol ketal and hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 91 of Z-hydroxymethylene 17a vinylandrostan-l7fl-ol-3-.

one.

EXAMPLE 93 2-[(l-pyrrolidyl)methylene] 17a ethyl 19-norandrostan-17fl-0l-3-0ne [1; R is H, R is C l-I X is H Y is CH Y is H, Z is OH, B=N is (CH N] can be prepared by replacing the Z-hydroxymethylene-4-androstcn-17fl-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-lh ethyl l9-norandrostan-l7fl-ol-3-one.

EXAMPLE 94 2-[(I pyrrolidyl)methylene]pregnane 3,20 dione [1; R is H, R is CH CO, X is H Y and Y are CH Z is H, B'=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17 3-ol-3-one in Example l by a molar equivalent amount of Z-hydroxymethylenepregnane-3,20-dione.

EXAMPLE 95 2-[(] pyrrolia'yl)methylene] 17a elhynylnndrostan-17fl-ol-3-one [l; R is H, R is CHEC, X is H Y and Y are CH Z is OH, B==N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7 8-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 17a ethynylandrostanl7fi-ol-3-one.

EXAMPLE 96 2-[(l pyrrolidyfi'methylene] 17oz aIlyI-4-androsten- -01-3-0r'1e [II; R is H, R is CHFCHCHQ, X is H Y and Y are CH Z is OH, B=N is (CH N] can be 19 prepared by replacing the 2-hydroxymethylene-4-androsten-l7B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene 17a-allyl 4 androstenl7B-ol-3-one.

EXAMPLE 97 2-[(] pyrr01idyl)methylene] 60c methyl-17a-pr0- pynyl 4 androsten-I7fl-0l-3-0ne can be prepared by replacing the 2-hydroxymethylene-4-androsten 17B ol-3- on'e in Example 1 by molar equivalent amount of 2- hydroxymethyleneoer-methyl 17a propynyl 4 androsten-17/i-ol-3-one.

EXAMPLE 98 2-[(] -pyrrolidyl)methylene] I7a-ethyl- 4,6-andrstadierz-17a-0I-3-0ne [IIa; R is H, R is C H X is H Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-andr0sten- 17fl-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-17a-ethyl-4,6-androstadien 17/3- ol-3-one.

EXAMPLE 99 2-[([ pyrrolr'dyl)methylene] 17a pr0pyl-4-andro- .rten-I7fl-0I-3-0ne [11; R is H, R is CH (CH X is H Y and Y are CH Z is OH, B=N is (Cl-I N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17B-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-l7a-propyl-4-androsten- 17/8-o1-3-one.

EXAMPLE 100 2-[(l pyrrolidyl)methylene] 17m pr0pargyl-4 ancIr0sten-17fi-0l-3-one [11; R is H, R is CHECCHQ, X is H Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-17fi-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymetbylene-17a-propargyl-4-androsten-17fi-ol-3-one.

EXAMPLE 101 2-l(I-pyrrolidyl)methylene] 19 norandrostan 17,9- ()l-3-0I1e [1; R is H, R is H, X is H Y is CH Y is H, Z is OH, B=N is (CH N] can be prepared by replacin the Z-hydroxymethylene 4 androsten-l7fi-ol-3- one in Example 1 by a molar equivalent amount of 2 hydroxymethylene-l9-norandrostan-17/9-ol-3-one.

EXAMPLE 102 2 [(J-pyrrolidyl)methylene] 17oz propylandrostan- 17,8-01-3-0/12 [1; R is H, R is CH (CH X is H Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-l7/3-ol-3-one in Example 1 by a molar equivalent amount of 2 hydroxymethylene 17 propylandrostan- 17,9-ol-3-one.

EXAMPLE 103 2-[(I-pyrrolidyl)methylene] 4 pregnene 1113,1701, 21-tri0l-3,20-dione 17,20;20,21 bismethylenedioxy derivative can be prepared by replacing the 2-hydroxy methylenel-androsten-17,8-ol-3-0ne in Example 1 by a molar equivalent amount of 2-hydroxymethylene-4-pregnene-1lfi,17a,21-triol 3,20 dione 17,20;20,21 bismethylenedioxy derivative.

EXAMPLE 104 2-[(l-pyrmlidyl)methylene] 9 fluoro 4 pregnene- I I 6,] 70r,2 I -lri01 3,20 dione 17,20;20,21 bismet/zylenedioxy derivative can be prepared by replacing the Z-hydroxymethylene-4-androsten I75 01 3 one in Example 1 by a molar equivalent amount of 2-l1ydroxyrnethylene 9 fluoro-4-pregnene-11p,17u,21-triol-3,20-dione l7,20;20,2l-bismethylenedioxy derivative.

EXAMPLE 105 2-[(1 -pyrrolidyl)methylene] 4 pregnene 17a,20- di0l-3-0ne [II; R is H, R is CH CH(OH), X is Bi Y 2% and Y are CH Z is OH, B=N is (CHflfNl can be prepared by replacing the Z-hydroxymethylenel-androsten-l7fi-ol-3-one in Example I by a molar equivalent amount of Z-hydroxymethylene-4-pregnene 17a,20-diol- 3-one.

EXAMPLE 106 2-[(] pyrrolidyl)methylene]-9a-fluoro 17oz methyl- 4-androsten-I7;8-0l-3,I1-dione can be prepared by replacing the 2-hydroxymethylene-4-androsten-17;3-ol-3-one in Example 1 by a molar equivalent amount of Z-hydroxymethylene-9rx-fluoro-l7a-methyl 4-androsten 17B ol- 3,1l-dione.

EXAMPLE 107 2[(I-pyrrolidyl)methylene] 4 androslene-llfiJ7/3- diol-3-one [11; R is H, R is H, X is (H)(OH), Y and Y are CH Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxymethylene-4-androsten-175-01- 3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene 4 androstene-l1,9,17B-diol-3-one.

EXAMPLE 109 2-[(I-pyrrolidyl)methylene]-17a methyl 19 nor-4- arrdr0sten-17/3-0l-3-0ne [II; R is H, R is CH;,, X is H 1 is CH;,, Y is H, Z is OH, B=N is (CH N] can be prepared by replacing the 2-hydroxy-methylene-4-androsten-l7 3-ol-3-one in Example 1 by a molar equivalent amount of 2-hydroxymethylene 17a-methy1-19-nor-4- androsten-l7fi-ol-3-one.

EXAMPLE 110 2-[(l-pyrrolidyl)methylene] I7a-propynylana'rostanl7/3-0I-3-0ne [1; R is H, R is CH C-=, X is H Y and Y' are CH Z is OH, B=N is (CH ).,N] can be prepared by replacing the Z-hydroxymethylene-4-androsten-Uri-ol- 3-one in Example 1 by a molar equivalent amount of 2- hydroxymethylene-l7a-propynylandrostan-17,8-01-3-one.

EXAMPLE 1 11 2-[(I-pyrrolidyl)methylene] 6-chI0r0-4,6-pregnadien- I7a-ol-3,20-di0rze can be prepared by reacting 6-chloro- 4,6-pregnadien-17a-ol-3,20-dione 20-monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting 2-hydroxy-methy1ene derivative with pyrrolidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 112 2-[(1pyrr01idyl)methylene] 6a-flu0r0 4-pregnene- I119,I7a,2I-triol-3,20-di0ne can be prepared by reacting 6u-fiuoro-4-pregnene 11,8,17a,21-triol 3,20-dione 20- monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting 2- hydroxymethylene derivative with pyrrolidine according to the manipulative procedure described above in Ex ample 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 1 13 2-[(I-pyrrolidyl)methylene] 6a-methyl 4-pregnen- 17a-ol-3,20-dione can be prepared by reacting Got-methyl- 4-pregnen-l7ot-ol-3,20 dione ZO-monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting Z-hydroxymethylene derivative with pyrrolidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 114 2-[(l-pyrrolidyl)methylene]-21-flu0r0 fi-merhyl 4,6- pregnadien-Ua-01-3,20-di0ne can be prepared by reacting 2l-fiuoro-6-methyl 4,6-pregnadien-l7u-ol-3,20-dione 20- monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting 2-hydroxymethylene derivative with pyrrolidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

EXAMPLE 1 EXAMPLE 1 16 2-[(l-pyrro/idyl)methylene] 6a,9a difluoro 16ozmethyl-4-pregnene IlfiJ7a,2I-tri0l-3,20-dione can be prepared by reacting 6a,9u-difluoro 16a-methyl-4-pregnene-ll5,17a,2l-triol-3,20-dione 20-monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting Z-hydroxymethylene derivative with pyrrolidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

Iclaim:

l. A 3-oxo-steroid having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in the 2-position by the grouping B=N-C(R)= wherein B=N is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, and R is selected from the group consisting of hydrogen and lower-alkyl.

2. A compound selected from the group consisting of (A) compounds having the formula wherein R represents a member of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, loweralkenyl, lower-alkynyl, acetyl, ketalized acetyl, hydroxy acetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl and 1- hydroxyethyl; X represents a member of the group consisting of H (H)(OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; Z represents a member of the group consisting of hydrogen and hydroxy, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and B=N represents a member of the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200; (B) carboxylic .22 acid esters of hydroxy containing compounds under (A); (C) acid-addition salts of (A) and (B); and (D) loweralkyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts of (A) and (B).

3. A compound according to claim 2 and having a double bond in the 4,5-position of the steroid nucleus.

.4. A compound according to claim 2 and having a double bond in each of the 4,5-position and the 6,7-position.

5. A compound having the formula wherein R represents lower-alkyl; and B=N represents di-loweraalkylamino.

6. A compound having the formula wherein R represents lower-alkyl; and B=N represents polymethylenimino having from 5 to 7 ring members.

7. A compound having the formula wherein B=N represents di-lower-alkylamino.

8. A compound having the formula wherein B=N represents polymethylenimino having from 5 to 7 ring members.

9. A compound having the formula R CH; 5

23 10. A compound having the formula A (I U wherein R represents lower-alkyl; and B=N represents polymethylenimino having from 5 to 7 ring members.

11. A compound having the formula wherein R represent lower-alkyl; and B=N represents di-lower-alkylamino-lower-alkylamino.

12. A compound having the formula wherein B N represents di-lower-alkylamino.

113. A compound having the formula H CH3 21. 2 (diethylaminomethylene) 17a methyletiocho1an-17p-ol-3-one,

22. 2 [(1 piperidyl)methylene] 17oz methyleitocholan-l7fl-ol-3-one.

23. 2 (dibutylaminomethylene) 17oz methyletiooholan-17fi-ol-3-one.

24. 2 [(3 -'acetamido 1 piperidyl)methylene]- l7u-methyletiocholan-l7fl-ol-3-one.

25. 2 (dibenzylaminomethylene) 17a methyletiochcolan-17B-ol-3-one.

26. The process for preparing a 3-oxo-steroid having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in the 2-position by the grouping B=N-C(R)== wherein B==N is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, and R is selected from the group consisting of hydrogen and loweralkyl, which comprises reacting a 3-oxo-steroid, having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in the 2-position by the grouping HOC(R)=, with a compound of the formula B NH.

27. The process for preparing a compound selected from the group consisting of (A) compounds having the formula wherein R represents a member of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl, loweralkenyl, lower-alkyny], acetyl, ketalized acetyl, hydroxyacetyl, ketalized hydroxyacetyl, 1,2-dihydroxyethyl and l-hydroxyethyl; X represents a member of the group consisting of H (H)(OH) and O; Y and Y represent members of the group consisting of hydrogen and inethyl; Z represents a member of the group consisting of "hydrogen and hydroxy, Z being restricted to hydroxy when R represents a member of the group consisting of hydrogen, lower-alkyl, lower-alkenyl and lower-alkynyl; and B=N represents a member of the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200; and (B) carboxylic acid esters of hydroxy containing compounds under (A), which comprises reacting a compound selected from the group consisting of (C) compounds having the formula and (D) carboxylic acid esters of compounds under (C) containing hydroxy groups in addition to that in the substituent in the 2-position, with a compound of the formula B=NH.

28. A process according to claim 27 wherein the steroid has a double bond in the 4,5-position.

29. A compound according to claim 1 in which the 3-oxo-steroid is a steroid of the pregnane series characteristic of the progestational and cortical hormones.

25 311. A compound selected from the group consisting of compounds having the formula:

and the 4-dehydro derivatives thereof wherein R is selected from the group consisting of hydrogen and methyl;

26 lower alkyl, lower alkenyl and lower alkynyl; R and R are selected from the group consisting of hydrogen, lower ailcyl, aralkyl containing up to eight carbon atoms and di-lower alkylaminolower alkyl, and R and R together with N represent a radical selected from the group consisting of piperidino, morpholino and pyrrolidino.

References Cited by the Examiner UNITED STATES PATENTS 3,213,116 10/1965 Moersch et a]. 260--397.4

LEWIS GOTTS, Primary Examiner. LESLIE H GASTON, Examiner.

R is selected from the group consisting of hydrogen, 15 E LANDE, m /1 's.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 265 ,686 August 9, 1966 Raymond 0. Clinton It is hereby Certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 45 to 54, the left-hand portion of the formula should appear as shown below instead of as in the patent:

column 8 line 71 for "101 5" read lOl 5 column 9, line 20, for "2-(diethylaminoethylene)" read 2- (diethylaminomethylene) column 13, line 47, for "allopregnene-S,lO-dione" read allopregnane-3,20dione column 19 line 15 for "l7c1-01-" read 17B-olcolumn 20 line 46, for "CH 2" read CHSCEC column 23 line 69 strike out "androstanl7B-ol-3-one Signed and sealed this 26th day of September 1967.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A 3-OXO-STEROID HAVING FROM SEVENTEEN TO ABOUT TWENTY-THREE CARBON ATOMS EXCLUSIVE OF ESTER RADICALS AND BEING FURTHER SUBSTITUTED IN THE 2-POSITION BY THE GROUPING B=N-C(R)= WHEREIN B=N IS SELECTED FROM THE GROUP CONSISTING OF PRIMARY AMINO, AND BASIC SECONDARY AND TERTIARY AMINO HAVING A MOLECULAR WEIGHT LESS THAN ABOUT 200, AND R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER-ALKYL.
 14. 2 - ((1 - PYRROLIDYL)METHYLENE) - 4 - ANDROSTEN17B-OL-3-ONE. 